Abstract Alterations of the mucosal barrier integrity resulting in translocation of microbial products from the intestinal lumen into the gut mucosa and then into the general circulation are characteristic to pathogenic HIV/SIV infections. HIV-associated enteropathy (diarrhea, weight loss, malnutrition, malabsorption and villous atrophy) was reported to occur early in the pandemic, but a direct causative relationship between GI dysfunction and HIV/SIV disease progression has never been established. The pathways involved in the development of HIV/SIV?related gut dysfunction are poorly understood too. In pathogenic HIV/SIV infections, intestinal dysfunction occurs very early and epithelial damage and CD4+ T cell depletion arise simultaneously and thus cannot be dissociated. It is therefore difficult to perform interventions aimed at studying the mechanisms of the mucosal damage in HIV/SIV-infected humans or macaques. Conversely, natural hosts of SIVs (such as African green monkyes, AGMs) are ideal models to dissect the relative contribution of different potential mechanisms of the mucosal dysfunction, because they maintain mucosal integrity throughout infection in spite of high levels of viral replication and, as a result, microbial translocation is absent throughout the course of SIV infection. Furthermore, mucosal CD4+ T cell depletion occurs transiently in AGMs, only during acute SIV infection. Our overarching objective being to understand the role of the GI dysfunction in the progression to AIDS and non-AIDS comorbidities, we designed a set of interventional approaches in SIVsab-infected AGMs to induce gastrointestinal dysfunction through mechanisms that were reported to impact GI integrity and disease progression in HIV infection: (i) alterations of the immune cell homeostasis through massive depletion of the CD4+ T cells; (ii) direct epithelial damage of the GI mucosa. We developed all the animal models necessary for this study (the Caribbean AGM model of nonprogressive SIV infection; the model of prolonged experimental depletion of CD4+ T cells using the CD4R1 monoclonal antibody; and a model of GI epithelial damage through administration of dextran sulfate sodium (DSS) to both uninfected macaques and SIV-infected AGMs). We have also developed multiple laboratory tools for the study of the mucosal dysfunction and its role in the pathogenesis of AIDS. Our specific aims are: (1) To assess the impact of CD4+ T cell depletion on the development of gut dysfunction and disease progression. (2) To directly assess the impact of intestinal epithelial damage on the development of gut dysfunction and disease progression. (3) To assess the impact of gut dysfunction generated by the combined action of CD4+ depletion and DSS-induced colitis on disease progression. The experiments proposed here will directly assess the contribution of GI dysfunction to HIV disease progression and will investigate some of the mechanisms of the HIV/SIV-related gut dysfunction. These studies will thus inform future therapeutic strategies aimed to preserve gut integrity and avoid disease progression.